rs200198847

Positions:

chrX-154350097-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_001110556.2(FLNA):c.7267C>T(p.Pro2423Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000616 in 1,210,258 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 240 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00044 ( 0 hom., 12 hem., cov: 25)

Exomes 𝑓: 0.00063 ( 0 hom. 228 hem. )

Consequence

FLNA
NM_001110556.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 2.67

Variant links:

Genes affected

FLNA (HGNC:3754): (filamin A) The protein encoded by this gene is an actin-binding protein that crosslinks actin filaments and links actin filaments to membrane glycoproteins. The encoded protein is involved in remodeling the cytoskeleton to effect changes in cell shape and migration. This protein interacts with integrins, transmembrane receptor complexes, and second messengers. Defects in this gene are a cause of several syndromes, including periventricular nodular heterotopias (PVNH1, PVNH4), otopalatodigital syndromes (OPD1, OPD2), frontometaphyseal dysplasia (FMD), Melnick-Needles syndrome (MNS), and X-linked congenital idiopathic intestinal pseudoobstruction (CIIPX). Two transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Mar 2009]

FLNA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), FLNA. . Gene score misZ 3.7802 (greater than the threshold 3.09). GenCC has associacion of gene with X-linked Ehlers-Danlos syndrome, terminal osseous dysplasia-pigmentary defects syndrome, FG syndrome 2, frontometaphyseal dysplasia, heterotopia, periventricular, X-linked dominant, Melnick-Needles syndrome, otopalatodigital syndrome type 2, periventricular nodular heterotopia, otopalatodigital syndrome type 1, intestinal pseudoobstruction, neuronal, chronic idiopathic, X-linked, familial thoracic aortic aneurysm and aortic dissection, congenital short bowel syndrome, frontometaphyseal dysplasia 1, cardiac valvular dysplasia, X-linked.

BP4

Computational evidence support a benign effect (MetaRNN=0.06486979).

BP6

Variant X-154350097-G-A is Benign according to our data. Variant chrX-154350097-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 213485.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154350097-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000435 (49/112632) while in subpopulation NFE AF= 0.000733 (39/53194). AF 95% confidence interval is 0.000551. There are 0 homozygotes in gnomad4. There are 12 alleles in male gnomad4 subpopulation. Median coverage is 25. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 12 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNA	NM_001110556.2 linkuse as main transcript	c.7267C>T	p.Pro2423Ser	missense_variant	45/48	ENST00000369850.10
FLNA	NM_001456.4 linkuse as main transcript	c.7243C>T	p.Pro2415Ser	missense_variant	44/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNA	ENST00000369850.10 linkuse as main transcript	c.7267C>T	p.Pro2423Ser	missense_variant	45/48	1	NM_001110556.2		P21333-1

Frequencies

GnomAD3 genomes

AF:

0.000435

AC:

AN:

112632

Hom.:

Cov.:

AF XY:

0.000345

AC XY:

AN XY:

34796

show subpopulations

Gnomad AFR

AF:

0.0000646

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000928

Gnomad ASJ

AF:

0.000754

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000641

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000733

Gnomad OTH

AF:

0.000664

GnomAD3 exomes

AF:

0.000435

AC:

AN:

181695

Hom.:

AF XY:

0.000444

AC XY:

AN XY:

67551

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000267

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000157

Gnomad FIN exome

AF:

0.000502

Gnomad NFE exome

AF:

0.000811

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000634

AC:

696

AN:

1097626

Hom.:

Cov.:

AF XY:

0.000628

AC XY:

228

AN XY:

363074

show subpopulations

Gnomad4 AFR exome

AF:

0.0000758

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000155

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000739

Gnomad4 FIN exome

AF:

0.000446

Gnomad4 NFE exome

AF:

0.000758

Gnomad4 OTH exome

AF:

0.000651

GnomAD4 genome

AF:

0.000435

AC:

AN:

112632

Hom.:

Cov.:

AF XY:

0.000345

AC XY:

AN XY:

34796

show subpopulations

Gnomad4 AFR

AF:

0.0000646

Gnomad4 AMR

AF:

0.0000928

Gnomad4 ASJ

AF:

0.000754

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000641

Gnomad4 NFE

AF:

0.000733

Gnomad4 OTH

AF:

0.000664

Alfa

AF:

0.000401

Hom.:

Bravo

AF:

0.000351

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00122

AC:

ExAC

AF:

0.000438

AC:

EpiCase

AF:

0.00109

EpiControl

AF:

0.000711

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Likely benign, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Dec 02, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 01, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 26, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 07, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 22, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 16, 2024	Variant summary: FLNA c.7267C>T (p.Pro2423Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00043 in 181695 control chromosomes. The observed variant frequency is approximately 1400 fold of the estimated maximal expected allele frequency for a pathogenic variant in FLNA causing Periventricular Nodular Heterotopia phenotype (3.1e-07), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.7267C>T in individuals affected with Periventricular Nodular Heterotopia and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 213485). Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 14, 2022	- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 12, 2018

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Melnick-Needles syndrome;C0265293:Frontometaphyseal dysplasia;C1844696:Oto-palato-digital syndrome, type II;C1848213:Heterotopia, periventricular, X-linked dominant

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

Melnick-Needles syndrome;C0262436:Cardiac valvular dysplasia, X-linked;C0265251:Oto-palato-digital syndrome, type I;C1844696:Oto-palato-digital syndrome, type II;C1845902:FG syndrome 2;C1846129:Terminal osseous dysplasia-pigmentary defects syndrome;C1848213:Heterotopia, periventricular, X-linked dominant;C2746068:Intestinal pseudoobstruction, neuronal, chronic idiopathic, X-linked;C4281559:Frontometaphyseal dysplasia 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 15, 2021

- -

FLNA-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 22, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Connective tissue disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Nov 01, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.45

T;.;.;.;.

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.95

D;D;.;D;D

M_CAP

Benign

0.033

MetaRNN

Benign

0.065

T;T;T;T;T

MetaSVM

Uncertain

0.23

MutationAssessor

Uncertain

2.1

M;.;.;.;.

MutationTaster

Benign

0.99

D;D;D;D;D

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-2.1

N;.;N;N;.

REVEL

Benign

0.28

Sift

Benign

0.057

T;.;D;D;.

Sift4G

Benign

0.67

T;T;T;T;T

Polyphen

0.024

B;.;B;B;.

Vest4

0.094

MVP

0.91

MPC

0.53

ClinPred

0.052

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.21

gMVP

0.36

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over